Head and neck squamous cell carcinoma (HNSCC) is a devastating disease that can destroy the structure and function of organs for deglutition, mastication, speech, taste, as well as other vital structures necessary for survival. These patients have shown significant immunologic dysfunctions in T and natural killer (NK) cell immunity that have been correlated with aggressive tumor behavior and to their poor survival. Therefore, our long-term goal is to devise new immunotherapeutic modalities to enhance anti-tumor immune responses in these patients. CD80 co-stimulatory molecule, one of the most potent known to date, provides vital signals for T cell activation and growth. Lack of T cell co-stimulation may lead to T cell anergy and immune unresponsiveness in the host. Transfection of CD80 into murine and human cell lines has been reported to promote antigen-specific cytotoxic T and NK-cell responses that result in immune recognition and destruction of tumors. Although most tumor tissues of non-hematopoietic origin including HNSCC do not express co-stimulatory molecules, keratinocytes do. The importance of endogenous CD80 expression on non-hematopoietic tumor cells and its regulation during tumor development and progression of HNSCC is not known. This significant gap in knowledge must be filled if we are to devise new immunotherapeutic modalities against HNSCC. The central hypothesis of this application is that endogenous CD80 expression is important in mediating tumor progression during early development of HNSCC by generating effective anti-tumor immunity, and that its expression is modulated by autocrine cytokines expressed during progression of HNSCC. The investigators have developed a new and unique murine model system of HNSCC in which endogenous CD80 expression by tumor cells correlates with progressor or regressor phenotypes of oral squamous cell carcinoma. The present study is based on preliminary data using this model system and proposes to use new immunologic and molecular techniques to: 1) establish the role of endogenous CD80 expression in mediating tumor progression of oral squamous cell carcinoma, 2) determine the role and regulatory mechanisms of cytokine-induced CD80 modulation in these tumors, and 3) determine the potential of CD80 expression as a prognostic tumor marker in patients with HNSCC. Understanding the role of endogenous CD80 and the mechanisms of its loss during development of HNSCC is necessary in order to develop novel therapeutic targets to prevent its loss and/or increase its expression on tumor cells. Such action may, potentially, increase anti-tumor immune responses and, therefore, survival of patients with this disease.